Etherlipids are amphipathic lipids with ether linkages connecting their hydrocarbons with their molecular backbones, and are synthetic analogs of platelet activating factor ("PAF"; 1-O-2-acetyl-sn-glycero-3-phosphocholine). PAF is an effector believed to be involved in a variety of physiological processes, such as inflammation, immune responses and allergic reactions.
Etherlipids can accumulate in cell membranes, following which the lipids may affect the cells in a number of ways. Cell membrane accumulation can lead to disturbance of membrane lipid organization by a detergent-like activity of etherlipids; membrane structure, and hence, cell stability can be disrupted by this activity. Phospholipid metabolism can also be disrupted, as the activities of several of the enzymes involved, e.g., CTP:phosphocholine cytidyl transferase, diacylglycerol kinase, sodium/potassium adenosine triphosphate phosphatase, acyl transferases, lysophospholipase, and phospholipases C and D, are inhibited in the presence of etherlipids. Etherlipids can also affect transmembrane signaling pathways, nutrient uptake, cellular differentiation and apoptosis.
Moreover, etherlipids are believed to be cytotoxic to cancer cells, and have been shown to be effective anticancer agents in animals see, for example, Lohmeyer and Bittman, 1994; Lu et al. (1994a); Lu et al. (1994b); Dietzfelbinger et al. (1993); Zeisig et al. (1993); Berdel (1991); Workman (1991); Workman et al. (1991); Bazill and Dexter (1990); Berdel (1990) Guivisdalsky et al. (1990a); Guivisdalsky et al. (1990b); Powis et al. (1990); Layton et al. (1980); Great Britain Patent No. 1,583,661; U.S. Pat. No. 3,752,886). However, etherlipids are generally not toxic to normal cells. Ether lipids' ability to act selectively on cancer cells is believed to be due to the cancer cells' lack of the alkyl cleavage enzymes necessary for hydrolysis of the lipids; the resulting intracellular lipid accumulation can disrupt the cells' functioning in a variety of ways. Normal cells typically possess these enzymes, and hence, to prevent their intracellular accumulation.
However, not all normal cells contain sufficient levels of alkyl cleavage enzymes to prevent intracellular ether lipid accumulation; cells which do not posses the requisite levels of the enzymes can be subject to the same disruptive effects of ether lipid action as are cancer cells. Red blood cells, for example, lack the requisite alkyl cleavage enzymes, and hence, are also subject to a detergent-like activity of ether lipids. Hemolysis which results from exposure of these cells to ether lipids having detergent-like activity can be a major drawback to therapeutic use of the ether lipids (see, for example, Houlihan et al., 1995).
A number of different approaches are potentially available for decreasing or eliminating such drug-induced toxicity. One such approach is to incorporate the drugs into lipid-based carriers, e.g., liposomes. Such carriers can buffer drug toxicity, for example, by sequestering the drug in the carrier such that the drug is unavailable for inducing toxicity. Lipid carriers can also buffer drug-induced toxicity by interacting with the drug such that the drug is then itself unable to interact with the cellular targets through which it exerts its cytotoxic effects. The carriers also maintain the ability of the drugs to be therapeutically effective when released therefrom, e.g., when the carriers are broken down in the vicinity of tumors.
This invention provides etherlipids in which the lipids' phosphate-based headgroups have been replaced with sugar moieties, the sugars themselves having been modified by substitution of one or more of their hydroxyl groups; applicants have found that such modification of etherlipids affords the modified etherlipids beneficial anticancer activity. Certain etherlipid analogues have been mentioned in the art, including O- and S-linked glucose and maltose substitutions of edelfosine's phosphorylcholine group. However, none of these analogues contain sugars modified by replacement of one or more hydroxyl groups.